Overcoming chemotherapy resistance in low-grade gliomas: A computational approach.

Low-grade gliomas are primary brain tumors that arise from glial cells and are usually treated with temozolomide (TMZ) as a chemotherapeutic option. They are often incurable, but patients have a prolonged survival. One of the shortcomings of the treatment is that patients eventually develop drug resistance. Recent findings show that persisters, cells that enter a dormancy state to resist treatment, play an important role in the development of resistance to TMZ. In this study we constructed a mathematical model of low-grade glioma response to TMZ incorporating a persister population. The model was able to describe the volumetric longitudinal dynamics, observed in routine FLAIR 3D sequences, of low-grade glioma patients acquiring TMZ resistance. We used the model to explore different TMZ administration protocols, first on virtual clones of real patients and afterwards on virtual patients preserving the relationships between parameters of real patients. In silico clinical trials showed that resistance development was deferred by protocols in which individual doses are administered after rest periods, rather than the 28-days cycle standard protocol. This led to median survival gains in virtual patients of more than 15 months when using resting periods between two and three weeks and agreed with recent experimental observations in animal models. Additionally, we tested adaptive variations of these new protocols, what showed a potential reduction in toxicity, but no survival gain. Our computational results highlight the need of further clinical trials that could obtain better results from treatment with TMZ in low grade gliomas.

Applied deep learning in neurosurgery: identifying cerebrospinal fluid (CSF) shunt systems in hydrocephalus patients.

BACKGROUND: Over the recent decades, the number of different manufacturers and models of cerebrospinal fluid shunt valves constantly increased. Proper identification of shunt valves on X-ray images is crucial to neurosurgeons and radiologists to derive further details of a specific shunt valve, such as opening pressure settings and MR scanning conditions. The main aim of this study is to evaluate the feasibility of an AI-assisted shunt valve detection system. METHODS: The dataset used contains 2070 anonymized images of ten different, commonly used shunt valve types. All images were acquired from skull X-rays or scout CT-images. The images were randomly split into a 80% training and 20% validation set. An implementation in Python with the FastAi library was used to train a convolutional neural network (CNN) using a transfer learning method on a pre-trained model. RESULTS: Overall, our model achieved an F1-score of 99% to predict the correct shunt valve model. F1-scores for individual shunt valves ranged from 92% for the Sophysa Sophy Mini SM8 to 100% for several other models. CONCLUSION: This technology has the potential to automatically detect different shunt valve models in a fast and precise way and may facilitate the identification of an unknown shunt valve on X-ray or CT scout images. The deep learning model we developed could be integrated into PACS systems or standalone mobile applications to enhance clinical workflows.

Exploring Novel Innovation Strategies to Close a Technology Gap in Neurosurgery: HORAO Crowdsourcing Campaign.

BACKGROUND: Scientific research is typically performed by expert individuals or groups who investigate potential solutions in a sequential manner. Given the current worldwide exponential increase in technical innovations, potential solutions for any new problem might already exist, even though they were developed to solve a different problem. Therefore, in crowdsourcing ideation, a research question is explained to a much larger group of individuals beyond the specialist community to obtain a multitude of diverse, outside-the-box solutions. These are then assessed in parallel by a group of experts for their capacity to solve the new problem. The 2 key problems in brain tumor surgery are the difficulty of discerning the exact border between a tumor and the surrounding brain, and the difficulty of identifying the function of a specific area of the brain. Both problems could be solved by a method that visualizes the highly organized fiber tracts within the brain; the absence of fibers would reveal the tumor, whereas the spatial orientation of the tracts would reveal the area's function. To raise awareness about our challenge of developing a means of intraoperative, real-time, noninvasive identification of fiber tracts and tumor borders to improve neurosurgical oncology, we turned to the crowd with a crowdsourcing ideation challenge. OBJECTIVE: Our objective was to evaluate the feasibility of a crowdsourcing ideation campaign for finding novel solutions to challenges in neuroscience. The purpose of this paper is to introduce our chosen crowdsourcing method and discuss it in the context of the current literature. METHODS: We ran a prize-based crowdsourcing ideation competition called HORAO on the commercial platform HeroX. Prize money previously collected through a crowdfunding campaign was offered as an incentive. Using a multistage approach, an expert jury first selected promising technical solutions based on broad, predefined criteria, coached the respective solvers in the second stage, and finally selected the winners in a conference setting. We performed a postchallenge web-based survey among the solvers crowd to find out about their backgrounds and demographics. RESULTS: Our web-based campaign reached more than 20,000 people (views). We received 45 proposals from 32 individuals and 7 teams, working in 26 countries on 4 continents. The postchallenge survey revealed that most of the submissions came from single solvers or teams working in engineering or the natural sciences, with additional submissions from other nonmedical fields. We engaged in further exchanges with 3 out of the 5 finalists and finally initiated a successful scientific collaboration with the winner of the challenge. CONCLUSIONS: This open innovation competition is the first of its kind in medical technology research. A prize-based crowdsourcing ideation campaign is a promising strategy for raising awareness about a specific problem, finding innovative solutions, and establishing new scientific collaborations beyond strictly disciplinary domains.

Computational design of improved standardized chemotherapy protocols for grade II oligodendrogliomas.

Here we put forward a mathematical model describing the response of low-grade (WHO grade II) oligodendrogliomas (LGO) to temozolomide (TMZ). The model describes the longitudinal volumetric dynamics of tumor response to TMZ of a cohort of 11 LGO patients treated with TMZ. After finding patient-specific parameters, different therapeutic strategies were tried computationally on the 'in-silico twins' of those patients. Chemotherapy schedules with larger-than-standard rest periods between consecutive cycles had either the same or better long-term efficacy than the standard 28-day cycles. The results were confirmed in a large trial of 2000 virtual patients. These long-cycle schemes would also have reduced toxicity and defer the appearance of resistances. On the basis of those results, a combination scheme consisting of five induction TMZ cycles given monthly plus 12 maintenance cycles given every three months was found to provide substantial survival benefits for the in-silico twins of the 11 LGO patients (median 5.69 years, range: 0.67 to 68.45 years) and in a large virtual trial including 2000 patients. We used 220 sets of experiments in-silico to show that a clinical trial incorporating 100 patients per arm (standard intensive treatment versus 5 + 12 scheme) could demonstrate the superiority of the novel scheme after a follow-up period of 10 years. Thus, the proposed treatment plan could be the basis for a standardized TMZ treatment for LGO patients with survival benefits.

Exploring Novel Funding Strategies for Innovative Medical Research: The HORAO Crowdfunding Campaign.

BACKGROUND: The rise of the internet and social media has boosted online crowdfunding as a novel strategy to raise funds for kick-starting projects, but it is rarely used in science. OBJECTIVE: We report on an online crowdfunding campaign launched in the context of the neuroscience project HORAO. The aim of HORAO was to develop a noninvasive real-time method to visualize neuronal fiber tracts during brain surgery in order to better delineate tumors and to identify crucial cerebral landmarks. The revenue from the crowdfunding campaign was to be used to sponsor a crowdsourcing campaign for the HORAO project. METHODS: We ran a 7-week reward-based crowdfunding campaign on a national crowdfunding platform, offering optional material and experiential rewards in return for a contribution toward raising our target of Swiss francs (CHF) 50,000 in financial support (roughly equivalent to US $50,000 at the time of the campaign). We used various owned media (websites and social media), as well as earned media (press releases and news articles) to raise awareness about our project. RESULTS: The production of an explanatory video took 60 hours, and 31 posts were published on social media (Facebook, Instagram, and Twitter). The campaign raised a total of CHF 69,109. Approximately half of all donations came from donors who forwent a reward (CHF 28,786, 48.74%); the other half came from donors who chose experiential and material rewards in similar proportions (CHF 14,958, 25.33% and CHF 15,315.69, 25.93%, respectively). Of those with an identifiable relationship to the crowdfunding team, patients and their relatives contributed the largest sum (CHF 17,820, 30.17%), followed by friends and family (CHF 9288, 15.73%) and work colleagues (CHF 6028, 10.21%), while 43.89% of funds came from donors who were either anonymous or had an unknown relationship to the crowdfunding team. Patients and their relatives made the largest donations, with a median value of CHF 200 (IQR 90). CONCLUSIONS: Crowdfunding proved to be a successful strategy to fund a neuroscience project and to raise awareness of a specific clinical problem. Focusing on potential donors with a personal interest in the issue, such as patients and their relatives in our project, is likely to increase funding success. Compared with traditional grant applications, new skills are needed to explain medical challenges to the crowd through video messages and social media.

What happens to the bone flap? Long-term outcome after reimplantation of cryoconserved bone flaps in a consecutive series of 92 patients.

BACKGROUND: Reimplantation of cryoconserved autologous bone flaps is a standard procedure after decompressive craniotomies. Aseptic necrosis and resorption are the most frequent complications of this procedure. At present there is no consensus regarding the definition of the relevant extent and indication for surgical revision. The objective of this retrospective analysis was to identify the incidence of bone flap resorption and the optimal duration of follow-up. METHODS: Between February 2009 and March 2012, 100 cryoconserved autologous bone flaps were reimplanted at the Department of Neurosurgery, Inselspital Bern. Three patients were not available for follow-up, and five patients died before follow-up. All patients underwent follow-up at 6 weeks and a second follow-up more than 12 months postoperatively. A clinical and CT-based score was developed for judgment of relevance and decision making for surgical revision. RESULTS: Mean follow-up period was 21.6 months postoperatively (range: 12 to 47 months); 48.9 % (45/92) of patients showed no signs of bone flap resorption, 20.7 % (19/92) showed minor resorption with no need for surgical revision, and 30.4 % (28/92) showed major resorption (in 4 % of these the bone flap was unstable or collapsed). CONCLUSIONS: Aseptic necrosis and resorption of reimplanted autologous bone flaps occurred more frequently in our series of patients than in most reports in the literature. Most cases were identified between 6 and 12 months postoperatively. Clinical observation or CT scans of patients with autologous bone flaps are recommended for at least 12 months. Patient-specific implants may be preferable to autologous bone flaps.

Polymorphous oligodendroglioma of Zülch revisited: a genetically heterogeneous group of anaplastic gliomas including tumors of bona fide oligodendroglial differentiation.

A polymorphous variant of oligodendroglioma was described by K.J. Zülch half a century ago, and is only very sporadically referred to in the subsequent literature. In particular, no comprehensive analysis with respect to clinical or genetic features of these tumors is available. From a current perspective, the term polymorphous oligodendroglioma (pO) may appear as contradictory in terms, as nuclear monotony is a histomorphological hallmark of oligodendrogliomas. For the purpose of this study, we defined pO as diffusely infiltrating gliomas felt to be of oligodendroglial rather than astrocytic differentiation and characterized by the presence of multinucleate tumor giant cells and/or nuclear pleomorphism. In a total of nine patients, we identified tumors consistent with this working definition. All tumors were high-grade. We characterized these with respect to clinical, histomorphological and genetic features. Despite clinical and genetic heterogeneity, we identified a subset of tumors of bona fide oligodendroglial differentiation as characterized by combined loss of heterozygosity of chromosome arms 1p and 19q (LOH 1p19q). Those tumors that lacked LOH 1p19q showed a high frequency of IDH1 mutations and loss of alpha thalassemia/mental retardation syndrome X-linked gene (ATRX) immunoreactivity, indicating a possible phenotypic convergence of true oligodendrogliomas and gliomas of the alternative lengthening of telomeres (ALT) pathway. p53 alterations were common irrespective of the 1p19q status. Histomorphologically, the tumors featured interspersed bizarre multinucleate giant tumor cells, while the background population varied from monotonous to significantly pleomorphic. Our findings indicate, that a rare polymorphous - or "giant cell" - variant of oligodendroglioma does indeed exist.

Intraoperative monopolar mapping during 5-ALA-guided resections of glioblastomas adjacent to motor eloquent areas: evaluation of resection rates and neurological outcome.

OBJECT: Resection of glioblastoma adjacent to motor cortex or subcortical motor pathways carries a high risk of both incomplete resection and postoperative motor deficits. Although the strategy of maximum safe resection is widely accepted, the rates of complete resection of enhancing tumor (CRET) and the exact causes for motor deficits (mechanical vs vascular) are not always known. The authors report the results of their concept of combining monopolar mapping and 5-aminolevulinic acid (5-ALA)-guided surgery in patients with glioblastoma adjacent to eloquent tissue. METHODS: The authors prospectively studied 72 consecutive patients who underwent 5-ALA-guided surgery for a glioblastoma adjacent to the corticospinal tract (CST; < 10 mm) with continuous dynamic monopolar motor mapping (short-train interstimulus interval 4.0 msec, pulse duration 500 µsec) coupled to an acoustic motor evoked potential (MEP) alarm. The extent of resection was determined based on early (< 48 hours) postoperative MRI findings. Motor function was assessed 1 day after surgery, at discharge, and at 3 months. RESULTS: Five patients were excluded because of nonadherence to protocol; thus, 67 patients were evaluated. The lowest motor threshold reached during individual surgery was as follows (motor threshold, number of patients): > 20 mA, n = 8; 11-20 mA, n = 13; 6-10 mA, n = 10; 4-5 mA, n = 13; and 1-3 mA, n = 23. Motor deterioration at postsurgical Day 1 and at discharge occurred in 30% (n = 20) and 10% (n = 7) of patients, respectively. At 3 months, 3 patients (4%) had a persisting postoperative motor deficit, 2 caused by vascular injury and 1 by mechanical injury. The rates of intra- and postoperative seizures were 1% and 0%, respectively. Complete resection of enhancing tumor was achieved in 73% of patients (49/67) despite proximity to the CST. CONCLUSIONS: A rather high rate of CRET can be achieved in glioblastomas in motor eloquent areas via a combination of 5-ALA for tumor identification and intraoperative mapping for distinguishing between presumed and actual motor eloquent tissues. Continuous dynamic mapping was found to be a very ergonomic technique that localizes the motor tissue early and reliably.

5-ALA complete resections go beyond MR contrast enhancement: shift corrected volumetric analysis of the extent of resection in surgery for glioblastoma.

BACKGROUND: The technique of 5-aminolevulinic acid (5-ALA) tumor fluorescence is increasingly used to improve visualization of tumor tissue and thereby to increase the rate of patients with gross total resections. In this study, we measured the resection volumes in patients who underwent 5-ALA-guided surgery for non-eloquent glioblastoma and compared them with the preoperative tumor volume. METHODS: We selected 13 patients who had received a complete resection according to intraoperative 5-ALA induced fluorescence and CRET according to post-operative T1 contrast-enhanced MRI. The volumes of pre-operative contrast enhancing tissue, post-operative resection cavity and resected tissue were determined through shift-corrected volumetric analysis. RESULTS: The mean resection cavity (29 cm(3)) was marginally smaller than the pre-operative contrast-enhancing tumor (39 cm(3), p = 0.32). However, the mean overall resection volume (84 cm(3)) was significantly larger than the pre-operative contrast-enhancing tumor (39 cm(3), p = 0.0087). This yields a mean volume of resected 5-ALA positive, but radiological non-enhancing tissue of 45 cm(3). The mean calculated rim of resected tissue surpassed pre-operative tumor diameter by 6 mm (range 0-10 mm). CONCLUSIONS: Results of the current study imply that (i) the resection cavity underestimates the volume of resected tissue and (ii) 5-ALA complete resections go significantly beyond the volume of pre-operative contrast-enhancing tumor bulk on MRI, indicating that 5-ALA also stains MRI non-enhancing tumor tissue. Use of 5-ALA may thus enable extension of coalescent tumor resection beyond radiologically evident tumor. The impact of this more extended resection method on time to progression and overall survival has not been determined, and potentially puts adjacent and functionally intact tissue at risk.

Intraoperative fabrication of patient-specific moulded implants for skull reconstruction: single-centre experience of 28 cases.

BACKGROUND: Intraoperatively fabricated polymethylmethacrylate (PMMA) implants based on computer-designed moulds were used to improve cosmetic results after hard tissue replacement. To assess the implant's cosmetic and functional results we performed both subjective and objective assessments. METHODS: This retrospective analysis was performed using a cohort of 28 patients who received PMMA implants between February 2009 and March 2012. The cosmetic and functional results were assessed using a patient questionnaire. Furthermore an objective volumetric subtraction score (0-100) was applied and implant thickness, as well as gaps and tiers, were measured. RESULTS: Patients mainly judged their cosmetic result as "good". Two of the 28 patients found their cosmetic result unfavourable. The functional result and stability was mainly judged to be good. Measurements of implant thickness showed a very high correlation with the thickness of the contralateral bone. Volumetric subtraction led to a median quality of 80 on a scale from 0 to 100. Median gaps around the margins of the implant were 1.5 mm parietally, 1.7 mm frontally and 3.5 mm fronto-orbitally, and median tiers were 1.2 mm, 0 mm and 0 mm respectively. The overall rate of surgical revisions was 10.7 % (three patients). Two patients suffered from wound healing disturbances (7.1 %). The overall complication rate was comparable to other reports in the literature. CONCLUSIONS: Implantation of intraoperatively fabricated patient-specific moulded implants is a cost-effective and safe technique leading to good clinical results with a low complication rate.

Training Performance Assessment for Intracranial Aneurysm Clipping Surgery Using a Patient-Specific Mixed-Reality Simulator: A Learning Curve Study.

BACKGROUND AND OBJECTIVES: The value of simulation-based training in medicine and surgery has been widely demonstrated. This study investigates the introduction and use of a new mixed-reality neurosurgical simulator in aneurysm clipping surgery, focusing on the learning curve and performance improvement. METHODS: Five true-scale craniotomy head models replicating patient-specific neuroanatomy, along with a mixed-reality simulator, a neurosurgical microscope, and a set of microsurgical instruments and clips, were used in the operation theater to simulate aneurysm microsurgery. Six neurosurgical residents participated in five video-recorded simulation sessions over 4 months. Complementary learning modalities were implemented between sessions. Thereafter, three blinded analysts reported on residents' use of the microscope, quality of manipulation, aneurysm occlusion, clipping techniques, and aneurysm rupture. Data were also captured regarding training time and clipping attempts. RESULTS: Over the course of training, clipping time and number of clipping attempts decreased significantly (P = .018, P = .032) and the microscopic skills improved (P = .027). Quality of manipulation and aneurysm occlusion scoring improved initially although the trend was interrupted because the spacing between sessions increased. Significant differences in clipping time and attempts were observed between the most and least challenging patient models (P = .005, P = .0125). The least challenging models presented higher rates of occlusion based on indocyanine green angiography evaluation from the simulator. CONCLUSION: The intracranial aneurysm clipping learning curve can be improved by implementing a new mixed-reality simulator in dedicated training programs. The simulator and the models enable comprehensive training under the guidance of a mentor.

A multi-center retrospective analysis of treatment effects and quality of life in adult patients with cranial ependymomas.

Long term quality of life data of adult patients harboring intracranial ependymomas have not been reported. The role of adjuvant radiation therapy in Grade II ependymomas is unclear and differs from study to study. We therefore sought to retrospectively analyze outcome and quality of life of adult patients that were operated on intracranial ependymomas at four different surgical centers in two countries. All patients were attempted to be contacted via telephone to assess quality of life (QoL) at the time of the telephone interview. The standard EORTC QoL Questionnaire C30 (EORTC QLQ-C30) and the EORTC QLQ-Brain Cancer Module (QLQ-BN20) were used. 64 adult patients with intracranial ependymomas were included in the study. The only factor that was associated with increased survival was age <55 years (p < 0.001). Supratentorial location was correlated with shorter progression free survival than infratentorial location (PFS; p = 0.048). In WHO Grade II tumors local irradiation did not lead to increased PFS (p = 0.888) or overall survival (p = 0.801). Even for incompletely resected Grade II tumors local irradiation did not lead to a benefit in PFS (p = 0.911). In a multivariate analysis of QoL, irradiated patients had significantly worse scores in the item "fatigue" (p = 0.037) than non-irradiated patients. Here we present QoL data of adult patients with intracranial ependymomas. Our data show that local radiation therapy may have long-term effects on patients' QoL. Since in the incompletely resected Grade II tumors local irradiation did not lead to a benefit in PFS in this retrospective study, prospective randomized studies are necessary. In addition to age, supratentorial tumor location is associated with a worse prognosis in adult ependymoma patients.

Dynamic Mixed-Reality Patient-Specific Aneurysm Clipping Simulation for Two Cases-A Feasibility Study.

BACKGROUND AND OBJECTIVE: Intracranial aneurysm (IA) clipping is a complex neurosurgical procedure which demands advanced technology to minimize risks and maximize patient outcomes. This study aims to evaluate the feasibility of training patient-specific microsurgical clipping procedures using a mixed-reality physical neurosurgical simulator for unruptured IA. METHODS: Two board-certified neurosurgeons were asked to simulate surgery in 2 patient-specific left-side unruptured middle cerebral artery-bifurcation IA models. The study was conducted in the operation theater under realistic conditions using a mixed-reality physical neurosurgical simulator. Time, procedural, and outcome-related information was collected. The participating neurosurgeons were encouraged to attempt all possible clipping strategies, even those deemed suboptimal, reporting the outcome of each strategy. Finally, to evaluate the feasibility and added value of integrating indocyanine green fluorescence angiography (ICG-FA) with the simulator, the ICG-FA videos for each clipping strategy were analyzed and compared with the reported clipping outcomes. RESULTS: Between 4 and 8, different clipping strategies were applied per aneurysm model; the number of strategies was higher in Patient Model 1 (6.5 ± 1.5) (more complex aneurysm) than in Patient Model 2 (5.0 ± 1.0). The clipping strategies differed between surgeons. At most, 53.5 minutes were necessary to complete each training session, but more than double the time was spent on the more complex aneurysm. Up to 53.8% (Patient Model 1) and 50% (Patient Model 2) of the attempted strategies were discarded by the neurosurgeons during the simulation. Evaluation of aneurysm occlusion through ICG-FA was specific, although sensitivity was poor. CONCLUSION: The present mixed-reality patient-specific simulator allows testing, anticipating, and discarding different aneurysm microsurgical clipping strategies regardless of the pathology complexity. Specific limitations should be considered regarding ICG-FA aneurysm inspection after clipping.

Space-expanding flap in decompressive hemicraniectomy for stroke.

OBJECTIVE: Decompressive hemicraniectomy (DCE) is the standard of care for space-occupying malignant infarction of the medial cerebral artery in suitable patients. After DCE, the brain is susceptible to trauma and at risk for the syndrome of the trephined. This study aimed to assess the feasibility of using temporary space-expanding flaps, implanted during DCE, to shield the brain from these risks while permitting the injured brain to expand. METHODS: The authors performed a prospective feasibility study to analyze the safety of space-expanding flaps in 10 patients undergoing DCE and evaluated clinical and radiological outcomes. RESULTS: The relatives of 1 patient withdrew consent, leaving 9 patients in the final analysis. No patients required removal of the space-expanding flap because of uncontrolled increase of intracranial pressure or infection. One patient required additional external ventricular drainage and 1 received mannitol. The mean (range) midline shift decreased from 6.67 (3-12) mm to 1.26 (0-2.6) mm after DCE with the space-expanding flap. The authors observed no cases of sinking skin flap syndrome, other complications, or deaths. One patient underwent further treatment due to infection of the reimplanted autologous bone flap. Two patients later refused cranioplasty, preferring to keep the space-expanding flap and thus avoid the potential risks of cranioplasty. CONCLUSIONS: This feasibility study showed that the concurrent use of space-expanding flaps appeared to be safe in patients who underwent DCE for malignant infarction of the medial cerebral artery. Moreover, space-expanding flaps may permit patients to avoid a second surgery for reimplantation of the autologous bone flap and the risks inherent to this procedure.

Robustness of the wide-field imaging Mueller polarimetry for brain tissue differentiation and white matter fiber tract identification in a surgery-like environment: an ex vivo study.

During neurooncological surgery, the visual differentiation of healthy and diseased tissue is often challenging. Wide-field imaging Muller polarimetry (IMP) is a promising technique for tissue discrimination and in-plane brain fiber tracking in an interventional setup. However, the intraoperative implementation of IMP requires realizing imaging in the presence of remanent blood, and complex surface topography resulting from the use of an ultrasonic cavitation device. We report on the impact of both factors on the quality of polarimetric images of the surgical resection cavities reproduced in fresh animal cadaveric brains. The robustness of IMP is observed under adverse experimental conditions, suggesting a feasible translation of IMP for in vivo neurosurgical applications.

Intraoperative Laser Speckle Contrast Imaging to Assess Vessel Flow in Neurosurgery: A Pilot Study.

BACKGROUND AND OBJECTIVES: Laser speckle contrast imaging (LSCI) has emerged as a promising tool for assessment of vessel flow during neurosurgery. We aimed to investigate the feasibility of visualizing vessel flow in the macrocirculation with a new fully microscope-integrated LSCI system and assess the validity and objectivity of findings compared with fluorescence angiography (FA). METHODS: This is a single-center prospective observational study enrolling adult patients requiring microsurgical treatment for brain vascular pathologies or brain tumors. Three independent raters, blinded toward findings of FA, reviewed regions of interest (ROIs) placed in exposed vessels and target structures. The primary end point was the validity of LSCI for assessment of vessel flow as measured by the agreement with FA. The secondary end point was objectivity, measured as the inter-rater agreement of LSCI findings. RESULTS: During 18 surgical procedures, 23 observations using FA and LSCI were captured simultaneously. Using LSCI, vessel flow was assessable in 62 (86.1%) and not assessable in 10 (13.9%) ROIs. The agreement between LSCI and FA was 86.1%, with an agreement coefficient of 0.85 (95% CI: 0.75-0.94). Disagreement between LSCI and FA was observed in the 10 ROIs that were not assessable. The agreement between ROIs that were assessable using LSCI and FA was 100%. The inter-rater agreement of LSCI findings was 87.9%, with an agreement coefficient of 0.86 (95% CI: 0.79-0.94). CONCLUSION: Fully microscope-integrated LSCI is feasible and has a high potential for clinical utility. Because of its characteristics, LSCI can be viewed as a full-field visual micro-Doppler that can be used as a complementary method to FA for assessing vessel flow during neurosurgery. Despite technical limitations related to the early development phase of the fully microscope-integrated system, we demonstrated reasonable validity and objectivity of findings compared with FA. Further research and refinement of the system may enhance its value in neurosurgical applications.

Decompressive hemicraniectomy in patients with supratentorial intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Decompressive craniectomy (DC) lowers intracranial pressure and improves outcome in patients with malignant middle cerebral artery stroke. Its usefulness in intracerebral hemorrhage (ICH) is unclear. The aim of this study was to analyze feasibility and safety of DC without clot evacuation in ICH. METHODS: We compared consecutive patients (November 2010-January 2012) with supratentorial ICH treated with DC without hematoma evacuation and matched controls treated by best medical treatment. DC measured at least 150 mm and included opening of the dura. We analyzed clinical (age, sex, pathogenesis, Glasgow Coma Scale, National Institutes of Health Stroke Scale), radiological (signs of herniation, side and size of hematoma, midline shift, hematoma expansion, distance to surface), and surgical (time to and indication for surgery) characteristics. Outcome at 6 months was dichotomized into good (modified Rankin Scale 0-4) and poor (modified Rankin Scale 5-6). RESULTS: Twelve patients (median age 48 years; interquartile range 35-58) with ICH were treated by DC. Median hematoma volume was 61.3 mL (interquartile range 37-83.5 mL) and median preoperative Glasgow Coma Scale was 8 (interquartile range 4.3-10). Four patients showed signs of herniation. Nine patients had good and 3 had poor outcomes. Three patients (25%) of the treatment group died versus 8 of 15 (53%) of the control group. There were 3 manageable complications related to DC. CONCLUSIONS: DC is feasible in patients with ICH. Based on this small cohort, DC may reduce mortality. Larger prospective cohorts are warranted to assess safety and efficacy.

Quantitative Analysis of the MGMT Methylation Status of Glioblastomas in Light of the 2021 WHO Classification.

Background: Glioblastomas with methylation of the promoter region of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene exhibit increased sensitivity to alkylating chemotherapy. Quantitative assessment of the MGMT promoter methylation status might provide additional prognostic information. The aim of our study was to determine a quantitative methylation threshold for better survival among patients with glioblastomas. Methods: We included consecutive patients ≥18 years treated at our department between 11/2010 and 08/2018 for a glioblastoma, IDH wildtype, undergoing quantitative MGMT promoter methylation analysis. The primary endpoint was overall survival. Results: A total of 321 patients were included. Median overall survival was 12.6 months. Kaplan−Meier and adjusted Cox regression analysis showed better survival for the groups with 16−30%, 31−60%, and 61−100% methylation. In contrast, survival in the group with 1−15% methylation was similar to those with unmethylated promoter regions. A secondary analysis confirmed this threshold. Conclusions: Better survival is observed in patients with glioblastomas with ≥16% methylation of the MGMT promoter region than with <16% methylation. Survival with tumors with 1−15% methylation is similar to with unmethylated tumors. Above 16% methylation, we found no additional benefit with increasing methylation.

Management of postoperative internal carotid artery intimal flap after carotid endarterectomy: a cohort study and systematic review.

OBJECTIVE: Postoperative internal carotid artery (ICA) intimal flap (IF) is a potential complication after carotid endarterectomy (CEA) for carotid artery stenosis. There are no clear recommendations in the current literature on the management of this condition due to sparse evidence. Some authors advocate carotid stent placement or reoperation, while others suggest watchful waiting. The aim of this study was to analyze incidence and management strategies of postoperative ICA-IF, and moreover, to put these findings into context with a systematic literature review. METHODS: The authors retrospectively reviewed all consecutive CEA cases performed at the University Hospital of Bern over a decade (January 2008 to December 2018). The incidence of postoperative ICA-IF, risk factors, management strategies, and outcomes were analyzed. These results were put into context with a systematic review following the PRISMA guidelines. RESULTS: A total of 725 CEAs were performed between January 2008 and December 2018. Postoperative ICA-IF was detected by routine duplex neurovascular ultrasound (NVUS) in 13 patients, corresponding to an incidence rate of 1.8% (95% CI 1.0%-3.1%). There were no associated intraluminal thrombi on the detected IF. Intraoperative shunt placement was used in 5.6% and one or more intima tack sutures were performed in 42.5% of the 725 cases. There was no significant association between intraoperative shunt placement and the occurrence of an IF (p > 0.99). Two patients (15.4%) with IF experienced a transient postoperative neurological deficit (transient ischemic attack). In these cases, the symptoms resolved spontaneously without any interventions or change in the antiplatelet regimen. All other cases (84.6%) with IF were asymptomatic. In 1 patient (7.7%) with IF, the antiplatelet treatment was switched from a mono- to a dual-antiaggregating regimen because the IF led to a stenosis > 70%; this patient remained asymptomatic. All cases of IFs were managed conservatively with close radiological follow-up evaluations, without reoperation or stenting of the ICA. All 13 IFs vanished spontaneously after a mean duration of 6.9 months (median 1.5 months, range 0.5-48 months). A systematic literature review revealed a postoperative ICA-IF incidence of 3.0% (95% CI 2.1%-4.1%) with relatively heterogenous management strategies. CONCLUSIONS: Postoperative ICA-IF is a rare finding after CEA. Conservative therapy with close NVUS follow-up evaluations appears to be an acceptable and safe management strategy for asymptomatic IFs without associated intraluminal thrombi.

Calcium-modulated chloride pathways contribute to chloride flux in murine cystic fibrosis-affected macrophages.

Cystic fibrosis (CF), a common lethal inherited disorder defined by ion transport abnormalities, chronic infection, and robust inflammation, is the result of mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a cAMP-activated chloride (Cl-) channel. Macrophages are reported to have impaired activity in CF. Previous studies suggest that Cl- transport is important for macrophage function; therefore, impaired Cl- secretion may underlie CF macrophage dysfunction. To determine whether alterations in Cl- transport exist in CF macrophages, Cl- efflux was measured using N-[ethoxycarbonylmethyl]- 6-methoxy-quinolinium bromide (MQAE), a fluorescent indicator dye. The contribution of CFTR was assessed by calculating Cl- flux in the presence and absence of cftr(inh)-172. The contribution of calcium (Ca(2+))-modulated Cl- pathways was assessed by examining Cl- flux with varied extracellular Ca(2+) concentrations or after treatment with carbachol or thapsigargin, agents that increase intracellular Ca(2+) levels. Our data demonstrate that CFTR contributed to Cl- efflux only in WT macrophages, while Ca(2+)-mediated pathways contributed to Cl- transport in CF and WT macrophages. Furthermore, CF macrophages demonstrated augmented Cl- efflux with increases in extracellular Ca(2+). Taken together, this suggests that Ca(2+)-mediated Cl- pathways are enhanced in CF macrophages compared with WT macrophages.